| Eukaryotic aspartyl protease | |||||||||
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| Structures of native and inhibited forms of human cathepsin D.[1] | |||||||||
| Identifiers | |||||||||
| Symbol | Asp | ||||||||
| Pfam | PF00026 | ||||||||
| InterPro | IPR001461 | ||||||||
| PROSITE | PDOC00128 | ||||||||
| SCOP | 1mpp | ||||||||
| OPM family | 108 | ||||||||
| OPM protein | 1lyb | ||||||||
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Aspartic proteases are a family of protease enzymes that use an aspartate residue for catalysis of their peptide substrates. In general, they have two highly-conserved aspartates in the active site and are optimally active at acidic pH. Nearly all known aspartyl proteases are inhibited by pepstatin.
Aspartic endopeptidases EC 3.4.23. of vertebrate, fungal and retroviral origin have been characterised[2]. More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin[3] and archaean preflagellin have been described[4][5].
Eukaryotic aspartic proteases include pepsins, cathepsins, and renins. They have a two-domain structure, arising from ancestral duplication. Retroviral and retrotransposon proteases (Pfam PF00077) are much smaller and appear to be homologous to a single domain of the eukaryotic aspartyl proteases. Each domain contributes a catalytic Asp residue, with an extended active site cleft localized between the two lobes of the molecule. One lobe has probably evolved from the other through a gene duplication event in the distant past. In modern-day enzymes, although the three-dimensional structures are very similar, the amino acid sequences are more divergent, except for the catalytic site motif, which is very conserved. The presence and position of disulfide bridges are other conserved features of aspartic peptidases.
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While a number of different mechanisms for aspartyl proteases have been proposed, the most widely accepted is a general acid-base mechanism involving coordination of a water molecule between the two highly-conserved aspartate residues.[6][7] One aspartate activates the water by abstracting a proton, enabling the water to attack the carbonyl carbon of the substrate scissile bond, generating a tetrahedral oxyanion intermediate. Rearrangement of this intermediate leads to protonation of the scissile amide.
| A1_Propeptide | |||||||||
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| crystal and molecular structures of human progastricsin at 1.62 angstroms resolution | |||||||||
| Identifiers | |||||||||
| Symbol | A1_Propeptide | ||||||||
| Pfam | PF07966 | ||||||||
| InterPro | IPR012848 | ||||||||
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Many eukaryotic aspartic endopeptidases (MEROPS peptidase family A1) are synthesised with signal and propeptides. The animal pepsin-like endopeptidase propeptides form a distinct family of propeptides, which contain a conserved motif approximately 30 residues long. In pepsinogen A, the first 11 residues of the mature pepsin sequence are displaced by residues of the propeptide. The propeptide contains two helices that block the active site cleft, in particular the conserved Asp11 residue, in pepsin, hydrogen bonds to a conserved Arg residue in the propeptide. This hydrogen bond stabilises the propeptide conformation and is probably responsible for triggering the conversion of pepsinogen to pepsin under acidic conditions.[8][9]
BACE; BACE1; BACE2; CTSD; CTSE; NAPSA; PGA5; PGC; REN;
Pepstatin is an inhibitor of aspartate proteases.
This article incorporates text from the public domain Pfam and InterPro IPR012848
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This article incorporates text from the public domain Pfam and InterPro IPR000036